1. Field of the Invention
The present invention relates to beta-lactamase inhibitors for medical use which are hydrolyzable in vivo and a process for the preparation thereof. More particularly, the present invention relates to 1,1-dioxopenicillanoyl oxymethyl D-6-[.alpha.-(methyleneamino) phenylacetamido]-penicillanate or pharmaceutically acceptable salts thereof represented by the following formula (I) and (I'): ##STR1## wherein Me is hydrochloride, sulfuric acid, phosphoric acid, maleic acid, succinic acid, methanesulfonic acid, or p-toluenesulfonic acid.
2. Description of the Prior Art
Sulbactam (penicillanic acid 1,1-dioxide) or pharmaceutically acceptable salts thereof are well known in the art as a kind of .beta.-lactamase-resistance antibiotic. Although sulbactam or pharmaceutically acceptable salts thereof alone are a poor inhibitor of .beta.-lactamases, when sulbactam or pharmaceutically acceptable salts thereof are reacted with .beta.-lactamase inhibiting antibiotics, the compounds exhibit a modest increase in inhibition of the enzymatic hydrolysis of antibiotics [FU, K.P. and NEU, H.C., Comparative Inhibition of .beta.-lactamase by novel .beta.-lactam compounds. Antimicrobial Agents and Chemotherapy 15, No.2, 171-176 (1979)].
Methanpicillin and its salts are disclosed in U.K. Patent No. 1,081,093, Korean Patent Publication 82-740 issued to the present inventor, and Belgium Patent 867,859 and have a marked increase in inhibition against gram-positive and gram-negative bacteria.
6-(aminoacyloxymethyl) penicillanic acid 1,1-dioxides as .beta.-lactamose inhibitors are disclosed in U.S. Pat. No. 4,503,040. While the compounds are effective in enhancing the activity of .beta.-lactam antibiotics in general, their preferred use is found in their combination with a penicillin or cephalosporin of established clinical utility, viz., amoxicillin, ampicillin, apalacillin, azlocillin, azthreonam, bacampicillin, carbenicillin, carbenicillin indanyl, carbenicillin phenyl, cefaclor, cefadroxil, cefaloram, cefamandole, cefamandole nafate, cefaparole, cefatrizine, cefazolin, cefmenoxime, cefonicid, cefodizime, cefoperazone, ceforanide, cefotaxime, cefotiam, cefotetan, cefoxitin, cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalothin, cephapirin, cephradine, cyclacillin, epicillin, furazlucillin, hetacillin, levopropylcillin, mecillinam, mezlocillin, penicillin G, penicillin V, phenethicillin, piperacillin, pirbenicillin, pivampicillin, sarmoxicillin, sarpicillin, suncillin, talampicillin or ticarcillin, or a pharmaceutically acceptable salt thereof. However, a pharmaceutical compound of sulbactam reacted with methampicillin has never been disclosed in the art and also the marked increase in activity of the compound in treating bacterial infections has never been disclosed.